Medulloblastoma (MB) is a highly malignant pediatric brain tumor with a 5-year survival rate of ~ 60%. Multiple signaling pathways, such as the sonic hedgehog (SHH) pathway, have been associated with MB tumorigenesis. Nevertheless, little is known about the mechanisms that regulate MB invasion and angiogenesis. Evidence is emerging that the unfolded protein response (UPR) activated in response to the tumor microenvironment plays a role in tumor development. Activation of the pancreatic endoplasmic reticulum kinase (PERK) branch of the UPR inhibits global protein biosynthesis, but stimulates the expression of certain stress-induced genes, such as vascular endothelial growth factor A (VEGF), by phosphorylating translation initiation factor 21 (eIF21). Data indicate that tumor cell-derived VEGF not only enhances angiogenesis but also acts directly on tumor cells in an autocrine manner to promote tumor growth and invasion. Interestingly, a recent study suggested a possible autocrine role of VEGF in MB growth. Our previous studies showed that enforced expression of interferon-3 in the central nervous system during development led to cerebellar dysplasia or MB. Importantly, our preliminary data suggested that activation of the PERK-eIF21 pathway facilitated interferon-3-induced MB formation. Thus, in this proposal, we will test the hypothesis that the PERK branch of the UPR promotes MB development by enhancing the tumor cell invasion and angiogenesis through the induction of VEGF, and renders MB cells resistant to chemotherapy. In the first specific aim, we will manipulate the activity of the PERK-eIF21 pathway using genetic approaches to determine whether the UPR influences MB formation in mice with heterozygous deficiency of patched1, a SHH receptor. We will also assess the effects of the PERK-eIF21 pathway on angiogenesis, tumor cell invasion and proliferation, and the expression of VEGF in the tumors. In the second specific aim, we will determine whether activation of the PERK-eIF21 pathway promotes MB cell migration and invasion through the induction of VEGF utilizing in vitro cell cultures. Moreover, we will determine whether the pro-tumorigenesis actions of PERK signaling are mediated by autocrine VEGF/VEGF receptor 2 signaling in MB cells utilizing an intracerebellar MB xenograft model. In the final specific aim, we will determine whether the UPR is activated in MB in human patients. Additionally, we will explore the role of the PERK-eIF21 pathway in MB resistance to chemotherapy and its underlying mechanisms. The significance of this proposed work is that it will uncover a novel mechanism responsible for MB invasion, angiogenesis, and chemotherapy resistance. The knowledge gained from these studies will have important implications for MB tumorigenesis and may lead to novel therapeutic strategies for treating this disease. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common malignant brain tumor in children. The goal of this project is to understand the role of the unfolded protein response in medulloblastoma development and chemotherapy resistance. This will provide novel insights into how medulloblastoma cells acquire the abilities to invade and promote angiogenesis and help identify new molecular targets for therapeutic intervention in patients with this disease.